Clinical Predictors of Liver Fibrosis Presence and Progression in Human Immunodeficiency Virus-Associated Nonalcoholic Fatty Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) affects more than one-third of people living with human immunodeficiency virus (HIV). Nonetheless, its natural history is poorly understood, including which patients are most likely to have a progressive disease course. METHODS: We leveraged a randomized trial of the growth hormone-releasing hormone analogue tesamorelin to treat NAFLD in HIV. Sixty-one participants with HIV-associated NAFLD were randomized to tesamorelin or placebo for 12 months with serial biopsies. RESULTS: In all participants with baseline biopsies (n = 58), 43% had hepatic fibrosis. Individuals with fibrosis had higher NAFLD Activity Score (NAS) (mean ± standard deviation [SD], 3.6 ± 2.0 vs 2.0 ± 0.8; P < .0001) and visceral fat content (mean ± SD, 284 ± 91 cm2 vs 212 ± 95 cm2; P = .005), but no difference in hepatic fat or body mass index. Among placebo-treated participants with paired biopsies (n = 24), 38% had hepatic fibrosis progression over 12 months. For each 25 cm2 higher visceral fat at baseline, odds of fibrosis progression increased by 37% (odds ratio, 1.37 [95% confidence interval, 1.03-2.07]). There was no difference in baseline NAS between fibrosis progressors and nonprogressors, though NAS rose over time in the progressor group (mean ± SD, 1.1 ± 0.8 vs -0.5 ± 0.6; P < .0001). CONCLUSIONS: In this longitudinal study of HIV-associated NAFLD, high rates of hepatic fibrosis and progression were observed. Visceral adiposity was identified as a novel predictor of worsening fibrosis. In contrast, baseline histologic characteristics did not relate to fibrosis progression.

Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease.

BACKGROUND: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD). METHODS: 92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways. RESULTS: Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways. CONCLUSIONS: Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation. Clinical Trials Registration. NCT02196831.

Effect of recombinant human growth hormone on liver fat content in young adults with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in young adults with obesity. Obesity is associated with relative growth hormone (GH) deficiency, and data from animal studies and from humans with pituitary GH deficiency suggest a role for GH deficiency in the pathogenesis of NAFLD. The effects of GH on NAFLD in those with obesity are unknown, however, prompting this pilot study to assess effects of GH administration on measures of NAFLD in young adults. METHODS: Twenty-four men and women aged 18-29 years with BMI ≥ 30 kg/m2 , hepatic fat fraction (HFF) ≥ 5% on proton magnetic resonance spectroscopy (1 H-MRS) and insulin-like growth factor 1 (IGF-1) z-score ≤ 0 were randomized to treatment with recombinant human GH (rhGH) versus no treatment for 24 weeks. The primary endpoint was change in HFF. RESULTS: Compared to no treatment, the effect size of rhGH on absolute HFF over 24 weeks was -3.3% (95% confidence interval: -7.8%, 1.2%; p = .14). At 24 weeks, HFF < 5% was achieved in 5 of 9 individuals receiving rhGH versus 1 of 9 individuals receiving no treatment (p = .04). rhGH did not significantly reduce ALT, AST or GGT. Serum IGF-1 increased as expected with rhGH treatment, and there were no changes in fasting lipids, C-reactive protein, fasting glucose or 2-h glucose following an oral glucose tolerance test. CONCLUSION: Data from this pilot study suggest that rhGH treatment in young adults with obesity and NAFLD may have benefits to reduce liver fat content, although larger studies are needed to confirm this effect.

Racial disparities in outcomes for extracorporeal membrane oxygenation in the United States.

BACKGROUND: Racial disparities in extracorporeal membrane oxygenation (ECMO) outcomes in patients with a broad set of indications are not well documented. METHODS: Adults requiring ECMO were identified in the 2016-2019 National Inpatient Sample. Patient and hospital characteristics, including mortality, clinical outcomes, and resource utilization were analyzed using multivariable regressions. RESULTS: Of 43,190 adult ECMO patients, 67.8% were classified as White, 18.1% Black, and 10.4% Hispanic. Although mortality for Whites declined from 47.5 to 41.0% (P = 0.002), it remained steady for others. Compared to White, Asian/Pacific Islander (PI) race was linked to increased odds of mortalty (AOR = 1.4, 95% CI = 1.1-2.0). Black race was associated with increased odds of acute kidney injury (AOR = 1.4, 95%-CI: 1.2-1.7), while Hispanic race was linked to neurologic complications (AOR 21.6; 95% CI 1.2-2.3). Black and Hispanic race were also associated with increased incremental costs. CONCLUSIONS: Race-based disparities in ECMO outcomes persist in the United States. Further work should aim to understand and mitigate the underlying reasons for such findings.

Venous thromboembolism in cancer surgery: A report from the nationwide readmissions database.

Background: The present study characterized the incidence of venous thromboembolism in a contemporary cohort of surgical oncology patients and its association with index hospitalization and postdischarge outcomes. Methods: Adults undergoing 7 major thoracic and abdominal cancer resections were identified in the 2016-2019 Nationwide Readmissions Database. Multivariable models stratified by operative subtype were developed to evaluate the association of venous thromboembolism with outcomes of interest. Results: Of an estimated 436,368 patients, venous thromboembolism was identified in 9,811 (2.2%) patients during index hospitalization. Esophageal (4.1%) and gastric (4.1%) resections exhibited the highest rates of venous thromboembolism, whereas pulmonary resection (1.0%) the lowest. Following adjustment, cancer resection type demonstrated the strongest association with venous thromboembolism development among all factors analyzed (adjusted odds ratio: 3.13, 95% confidence interval: 2.60-3.78). Diagnosis of venous thromboembolism was associated with increased mortality (10.2%, 95% confidence interval: 9.4-11.1 vs 1.7, 95% confidence interval: 1.6-1.7) and prolonged index hospital stay (19.5 days, 95% confidence interval: 19.1-20.0 vs 7.5, 95% confidence interval: 7.4-7.5). Of patients who survived index hospitalization, venous thromboembolism occurrence was associated with increased risk of nonhome discharge (56.4%, 95% confidence interval: 54.7-58.0 vs 14.4, 95% confidence interval: 14.2-14.7) and readmission (30.0%, 95% confidence interval: 28.5-31.1 vs 16.9, 95% confidence interval: 16.7-17.1). Additionally, venous thromboembolism substantially increased index hospitalization ($40,000, 95% confidence interval: $38,000-$42,000) and readmission costs ($3,200, 95% confidence interval: $1,700-$4,700). Conclusion: Rates of venous thromboembolism remain high in surgical oncology patients, with cancer resection type as a major predictor of venous thromboembolism incidence. Venous thromboembolism was associated with inferior clinical and financial outcomes that extended beyond discharge. These findings underscore the importance of continued vigilance and procedure-specific prophylaxis measures.

Pericardiocentesis or surgical drainage: A national comparison of clinical outcomes and resource use.

BACKGROUND: While institutional series have sought to define the optimal strategy for drainage of pericardial effusions, large-scale comparisons remain lacking. Using a nationally representative sample, the present study examined clinical and financial outcomes following pericardiocentesis (PC) and surgical drainage (SD) in patients admitted for pericardial effusion and tamponade. METHODS: Adults undergoing PC or SD within 2 days of admission for non-surgically related pericardial effusion or tamponade were identified in the 2016-2019 Nationwide Readmissions Database. Multivariable logistic and linear models were developed to evaluate the association between intervention type and outcomes. The primary outcome of interest was mortality while secondary endpoints included reintervention, periprocedural complications, hospital length of stay (LOS), hospitalization costs and 30-day non-elective readmission. RESULTS: Of an estimated 44,637 records meeting inclusion criteria, 28,862 (64.7%) underwent PC while the remainder underwent SD for initial management of pericardial effusion or tamponade. PC was associated with significantly increased odds of in-hospital mortality, reintervention and 30-day readmission relative to SD. PC was also associated with greater odds of cardiac complications but lower odds of infection, respiratory failure and blood transfusions compared to SD. Although PC was associated with shorter index hospital length of stay and costs, the two strategies yielded similar 30-day cumulative costs. CONCLUSION: Management of pericardial effusion with PC is associated with greater odds of mortality, reintervention and 30-day readmission but similar 30-day cumulative costs compared to SD. In the setting of adequate hospital capability and operator expertise, SD is a reasonable initial treatment strategy for pericardial effusion.

Impact of opioid use disorder on resource utilization and readmissions after operative trauma.

BACKGROUND: Although patients with opioid use disorder have been shown to be more susceptible to traumatic injury, the impact of opioid use disorder after trauma-related admission remains poorly characterized. The present nationally representative study evaluated the association of opioid use disorder on clinical outcomes after traumatic injury warranting operative intervention. METHODS: The 2010 to 2018 Nationwide Readmissions Database was used to identify adult trauma victims who underwent major operative procedures. Injury severity was quantified using International Classification of Diseases Trauma Mortality Prediction Model. Entropy balancing was used to adjust for intergroup differences. Multivariable regression models were developed to assess the association of opioid use disorder on in-hospital mortality, perioperative complications, resource utilization, and readmissions. RESULTS: Of an estimated 5,089,003 hospitalizations, 54,097 (1.06%) had a diagnosis of opioid use disorder with increasing prevalence during the study period. Compared with others, opioid use disorder had a lower proportion of extremity injuries and falls but greater predicted mortality measured by Trauma Mortality Prediction Model. After adjustment, opioid use disorder was associated with decreased odds of in-hospital mortality (adjusted odds ratio: 0.61; 95% confidence interval, 0.53-0.70) but had greater likelihood of pneumonia, infectious complications, and acute kidney injury. Additionally, opioid use disorder was associated with longer hospitalization duration as well as greater index costs and risk of readmission within 30 days (adjusted odds ratio: 1.36; 95% confidence interval, 1.25-1.49). CONCLUSION: Opioid use disorder in operative trauma has significantly increased in prevalence and is associated with decreased in-hospital index mortality but greater resource utilization and readmission.

Disparities in cardiac arrest and failure to rescue after major elective noncardiac operations.

BACKGROUND: Contemporary large-scale studies examining demographic and surgical factors associated with perioperative cardiac arrest and its associated outcomes are sparse. METHODS: Adults undergoing elective pancreatectomy, hepatectomy, lung resection, colectomy, gastrectomy, esophagectomy, abdominal aortic aneurysm repair, or hip replacement were identified between 2005 and 2018 using the National Inpatient Sample. Factors associated with cardiac arrest were of primary interest, while failure to rescue was also considered. Risk-adjusted outcomes were analyzed using logistic regressions to ascertain adjusted odds ratios as selected with Elastic Net methodology. RESULTS: Of an estimated 7,216,531 hospitalizations for major elective operations, 21,496 (0.3%) had cardiac arrest. The incidence of cardiac arrest decreased from 0.4% in 2005 to 0.3% in 2018, as did failure to rescue (65.4%-53.2%, P < .001). Factors including increased age (adjusted odds ratios: 1.02/year; 95% confidence interval, 1.01-1.02), higher Elixhauser comorbidity score (adjusted odds ratios: 1.46/point; 95% confidence interval, 1.44-1.49), abdominal aortic aneurysm repair (adjusted odds ratios: 1.67, 95% confidence interval, 1.25-2.23, reference: esophagectomy), and Black race (adjusted odds ratios: 1.60; 95% confidence interval, 1.43-1.80, reference: White) were independently associated with increased cardiac arrest. Furthermore, private insurance (private: adjusted odds ratios: 0.78; 95% confidence interval, 0.66-0.93, reference: Medicaid) and the highest income quartile (highest: adjusted odds ratios: 0.83; 95% confidence interval, 0.75-0.92, reference: lowest) were associated with lower adjusted odds of cardiac arrest. After cardiac arrest, Black race (adjusted odds ratios: 1.26; 95% CI, 1.02-1.56, reference: White) maintained increased adjusted odds of failure to rescue. CONCLUSION: Despite a reduction in the incidence of cardiac arrest and an associated improvement in survival, racial and socioeconomic disparities influence outcomes. These findings may advise policy changes to encourage equity in outcomes for those undergoing major elective operations.

Impact of delayed intervention on clinical outcomes following traumatic hip fracture in the elderly: A national analysis.

The present study sought to evaluate clinical outcomes of delayed intervention following hip fractures. Adults (≥60 years) who underwent operative intervention for hip fracture following traumatic fall were identified using the 2008-2018 National Inpatient Sample. Patients were classified as Delayed if repair was >48 h after admission and otherwise considered Early. Of an estimated 1,942,905 patients, 148,441 (7.6%) were Delayed. Delayed more commonly suffered neck fractures, underwent hip arthroplasty and were managed at low-volume hospitals. After adjustment, delayed operation was associated with greater likelihood of mortality (adjusted odds ratio (AOR): 1.28, 95% CI: 1.17-1.40), studied complications, hospitalization duration and costs.

Cocaine Reduces the Neuronal Population While Upregulating Dopamine D2-Receptor-Expressing Neurons in Brain Reward Regions: Sex-Effects.

Addiction to cocaine is associated with dysfunction of the dopamine mesocortical system including impaired dopamine-2 receptor (D2r) signaling. However, the effects of chronic cocaine on neuronal adaptations in this system have not been systematically examined and data available is mostly from males. Here, we investigated changes in the total neuronal density and relative concentration of D2r-expressing neurons in the medial prefrontal cortex (mPFC), dorsal striatum (Dstr), nucleus accumbens (NAc), and ventral tegmental area (VTA) in both male and female mice passively exposed to cocaine for two weeks. In parallel experiments, we measured mRNA levels for Drd2 and for opioid peptides (mPenk and mPdyn). Through a combination of large field of view fluorescent imaging with BAC transgenic D2r-eGFP mice and immunostaining, we observed that cocaine exposed mice had a higher density of D2r-positive cells that was most prominent in mPFC and VTA and larger for females than for males. This occurred amidst an overall significant decrease in neuronal density (measured with NeuN) in both sexes. However, increases in Drd2 mRNA levels with cocaine were only observed in mPFC and Dstr in females, which might reflect the limited sensitivity of the method. Our findings, which contrast with previous findings of cocaine-induced downregulation of D2r binding availability, could reflect a phenotypic shift in neurons that did not previously express Drd2 and merits further investigation. Additionally, the neuronal loss particularly in mPFC with chronic cocaine might contribute to the cognitive impairments observed with cocaine use disorder.

Placental Vascular Abnormalities in Association With Prenatal and Long-Term Health Characteristics Among HIV-Exposed Uninfected Adolescents and Young Adults.

BACKGROUND: HIV-exposed uninfected (HEU) individuals are predisposed to adverse health outcomes, which in part may stem from the influence of an altered intrauterine milieu on fetal programming. The placenta serves as a readout for the effects of the maternal environment on the developing fetus and may itself contribute to the pathogenesis of disease. SETTING: US academic health system. METHODS: We leveraged a previously established registry-based cohort of HEU adolescents and young adults to identify 26 subjects for whom placental histopathology was available. We further obtained placental tissue from 29 HIV-unexposed pregnancies for comparison. We examined differences in placental histopathology between the groups and related villous vascularity in the HEU group to prenatal maternal characteristics and long-term health outcomes. RESULTS: Placentas from HEU pregnancies demonstrated a higher blood vessel count per villus as compared with controls (5.9 ± 1.0 vs. 5.4 ± 0.8; P = 0.05), which was independent of maternal prenatal age, race, body mass index, smoking status, hemoglobin, and gestational age. Furthermore, within the HEU group, lower CD4+ T-cell count during pregnancy was associated with greater placental vascularity (r = -0.44; P = 0.03). No significant relationships were observed between placental blood vessel count per villus and body mass index z-score or reactive airway disease among HEU individuals later in life. CONCLUSIONS: Placentas from HEU pregnancies demonstrated increased villous vascularity compared with HIV-unexposed controls in proportion to the severity of maternal immune dysfunction. Further studies are needed to examine intrauterine exposure to hypoxia as a potential mechanism of fetal programming in HIV.

Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review.

Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in individuals with obesity. Although multiple pharmacotherapeutics are in development, currently there are limited strategies specifically targeting NAFLD. This systematic review summarizes the existing literature on hepatic effects of medications used for weight loss. Glucagon-like peptide 1 (GLP-1) agonists are the best-studied in this regard, and evidence consistently demonstrates reduction in liver fat content, sometimes accompanied by improvements in histological features of steatohepatitis and reductions in serum markers of hepatic injury such as alanine aminotransferase (ALT). It remains unclear whether these benefits are independent of the weight loss caused by these agents. Literature is limited regarding effects of orlistat, but a small number of reports suggest that orlistat reduces liver fat content and improves histologic features of NASH, benefits which may also be driven primarily by weight loss. A sizeable body of literature on hepatic effects of metformin yields mixed results, with a probability of modest benefit, but no consistent signal for strong benefit. There are insufficient data on hepatic effects of topiramate, phentermine, naltrexone, bupropion, and lorcaserin. Finally, a few studies to date suggest that sodium-glucose co-transporter-2 (SGLT2) inhibitors may reduce liver fat content and cause modest reductions in ALT, but further study is needed to better characterize these effects. Based on available data, GLP-1 agonists have the strongest evidence base demonstrating beneficial effects on NAFLD, but it is not clear if any weight loss medication has effects on NAFLD superior to those of nutritional modification and exercise alone.

In vivo detection of tumor boundary using ultrahigh-resolution optical coherence angiography and fluorescence imaging.

Accurate detection of early tumor margin is of great preclinical and clinical implications for predicting the survival rate of subjects and assessing the response of tumor microenvironment to chemotherapy or radiation therapy. Here, we report a multimodality optical imaging study on in vivo detection of tumor boundary by analyzing neoangiogenesis of tumor microenvironment (microangiography), microcirculatory blood flow (optical Doppler tomography) and tumor proliferation (green fluorescent protein [GFP] fluorescence). Microangiography demonstrates superior sensitivity (77.7 ± 6.4%) and specificity (98.2 ± 1.7%) over other imaging technologies (eg, optical coherence tomography) for tumor margin detection. Additionally, we report longitudinal in vivo imaging of tumor progression and show that the abrupt tumor cell proliferation did not occur until local capillary density and cerebral blood flow reached their peak approximately 2 weeks after tumor implantation. The unique capability of longitudinal multimodality imaging of tumor angiogenesis may provide new insights in tumor biology and in vivo assessment of the treatment effects on anti-angiogenesis therapy for brain cancer.

Association of In Utero HIV Exposure With Obesity and Reactive Airway Disease in HIV-Negative Adolescents and Young Adults.

BACKGROUND: HIV-negative individuals with in utero HIV exposure represent an emerging population, exceeding 18 million people worldwide. Long-term clinical outcomes among HIV-exposed uninfected (HEU) individuals into adolescence and young adulthood remain unknown. SETTING: US academic health system. METHODS: In this observational cohort study, we leveraged a patient data registry to identify 50 HEU adolescents and young adults. We also identified 141 HIV-unexposed controls that were matched to HEU subjects up to 3:1 on age of last encounter (±2 years), birthdate (±5 years), sex, race/ethnicity, and zip code. All subjects were born since January 1, 1990, with medical records available into adolescence and young adulthood. Primary outcomes were most recent body mass index (BMI) z-score and presence of reactive airway disease (RAD). Records were manually reviewed to extract health information. RESULTS: Fifty HEU adolescents and young adults (18 ± 3 years, 54% men) and 141 matched controls (19 ± 3 years, 54% men) were compared. HEU individuals had a higher BMI z-score (1.12 ± 1.08 vs. 0.73 ± 1.09, P = 0.03) and an increased prevalence of obesity (42% vs. 22%, P = 0.009) compared with controls. HEU subjects also had a higher prevalence of RAD vs. controls (40% vs. 23%, P = 0.03). These differences persisted on adjusting for demographic, socioeconomic, maternal, and birth-related factors. Maternal prenatal CD4 T-cell count was inversely associated with BMI z-score among HEU adolescents (r = -0.47, P = 0.01). CONCLUSIONS: HEU adolescents and young adults exhibited a heightened prevalence of obesity and RAD compared with HIV-unexposed controls. Additional studies are needed to optimize care for the expanding population of HEU individuals transitioning to adulthood.

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.

Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people with HIV and there are no proven pharmacological treatments for the disease in this population. We assessed the effects of tesamorelin on liver fat and histology in people with HIV and NAFLD. METHODS: This randomised, double-blind, multicentre study with identical placebo as a comparator was done in a hospital and a medical research centre in the USA. People with HIV infection and a hepatic fat fraction (HFF) of 5% or more by proton magnetic resonance spectroscopy were eligible. Participants were randomly assigned (1:1) to receive either tesamorelin 2 mg once daily or placebo once daily for 12 months, followed by a 6-month open-label phase during which all participants received tesamorelin 2 mg daily. The randomisation list was prepared by the study statistician using a permuted block algorithm within each stratum with randomly varying block sizes. The primary endpoint was change in HFF between baseline and 12 months. The primary safety endpoint was glucose. Analysis was by intention to treat using all available data. This trial is registered with ClinicalTrials.gov, number NCT02196831. FINDINGS: 61 patients were enrolled between Aug 20, 2015, and Jan 16, 2019, of whom 30 received tesamorelin and 30 received placebo. Patients receiving tesamorelin had a greater reduction of HFF than did patients receiving placebo, with an absolute effect size of -4·1% (95% CI -7·6 to -0·7, p=0·018), corresponding to a -37% (95% CI -67 to -7, p=0·016) relative reduction from baseline. After 12 months, 35% of individuals receiving tesamorelin and 4% receiving placebo had a HFF of less than 5% (p=0·0069). Changes in fasting glucose and glycated haemoglobin were not different between groups at 12 months. Individuals in the tesamorelin group experienced more localised injection site complaints than those in the placebo group, though none were judged to be serious. INTERPRETATION: Tesamorelin might be beneficial in people with HIV and NAFLD. Further studies are needed to determine the long-term effects of tesamorelin on liver histology. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.